一骚烧、CXCL12-producing vascular endothelial niches control acute T cell leukemia maintenance（重點參考文獻(xiàn)）

1主经、（P2）Similarities between leukemia-initiating cells (LIC) and hematopoietic stem cells (HSC) have raised the hypothesis that LIC require a specialized microenvironment to survive, and that disrupting this niche may be a promising therapeutic strategy
2惑艇、（P3）CXCL12 is expressed by numerous lineages including endothelial cells, perivascular cells and osteoblasts
3征堪、（P4）To investigate whether leukemic cells preferentially localize with osteoblasts or the vasculature (i.e. bone marrow sinusoids) early in disease, VEcad-cre;LoxP-tdTomato, Leprcre;LoxP-tdTomato and Col2.3-cre;LoxP-tdTomato hosts were sublethally irradiated and injected with 1 million GFP+ T-ALL cells. One week later, two photon imaging analysis showed that leukemic cells associated with VE-Cad+ and Lepr+ cells, but not osteoblasts
4管毙、（P4）Moreover, when the mice were sacrificed on day 25 post-transplantation, we observed a significant reduction in tumor burden compared to controls when CXCL12 was absent in vascular cells
5嚎莉、（P5）However, when we assessed CXCR4 surface expression on patient T cell leukemia cells and healthy control T cells, we found that T-ALL cells expressed higher levels of CXCR4 than CD4+CD3+ or CD8+CD3+ T cells from the peripheral blood of healthy controls
6米酬、（P7）Initial analysis of the Cxcr4-targeted data revealed changes in genes significant for early T cell development and T-ALL induction and progression such as Cdk4, Notch3, Il2ra (CD25), Ptcra, and Cdkn2a. Although altered expression of some of these genes could account for the T-ALL phenotype
7、（P8）T cell development is profoundly dependent, at different stages, on signaling through Notch1, pre-TCR/TCR, and IL-7R
8趋箩、(P8)CXCR4 retains normal developing B and myeloid cells in the bone marrow. B and myeloid leukemia cells appear to share this dependence on CXCR4, as CXCR4 antagonism mobilizes these cells out of the bone marrow and into the bloodstream, depriving them of stromal support and exposing them to co-administered chemotherapeutic drugs.
9赃额、（P9）Indeed, we have observed high surface CXCR4 on all T-ALL subtypes, including early T precursor (ETP-ALL), a more immature and high-risk disease subtype